Genomic instability is a conserved hallmark of eukaryotic aging and increased DNA damage load has been shown to promote both cancer and age-related diseases. We have shown previously that the histone deacetylase SIRT1 is recruited to sites of DNA double-strand breaks (DSBs), and that SIRT1 function is required for efficient DSB repair in a cell-based assay. To investigate if SIRT1 expression influences mutation load in vivo, we have generated compound transgenic mouse strains that either lack or overexpress SIRT1, in a temporally or spatially regulated manner, and further carry a LacZ reporter allele designed to reveal DNA mutation and chromosomal rearrangements due to DSBs. These mice are currently housed in separate cohorts and will be analyzed at varying time points to determine age-associated changes in mutation load in the presence or absence of SIRT1. The effect of exogenous mutagens, specifically ionizing radiation, will also be investigated. SIRT1 is associated with many of the beneficial effect of a dietary regimen called caloric restriction (CR) and SIRT1 function can be manipulated with several small molecules, some of which are in clinical trials. CR was shown to decrease tumorigenesis, both with age and in response to mutagens, and it will be interesting to see if SIRT1 is involved in this aspect of CR, thereby opening novel avenues of therapeutic intervention with regard to the age-related increase in chromosomal damage and concomitant cancer formation.